Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda -7/IL-24–mediated toxicity

• DOI: 10.1073/pnas.1100769108
• Publication Date: 2011-05-10T06:10:02Z
• Authors: Rupesh Dash; Belal Azab; Bridget A. Quinn; Xuening Shen; Xiang-Yang Wang; Swadesh K. Das; Mohamed Rahmani; Jun Wei; Michael Hedvat; Paul Dent; Igor P. Dmitriev; David T. Curiel; Steven Grant; Bainan Wu; John L. Stebbins; Maurizio Pellecchia; John C. Reed; Devanand Sarkar; Paul B. Fisher
• Keywords: Male; 0301 basic medicine; Interleukins; Gossypol; Mice, Nude; Prostatic Neoplasms; Apoptosis; Genetic Therapy; Transfection; Xenograft Model Antitumor Assays; 3. Good health; Mice; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Animals; Humans; Myeloid Cell Leukemia Sequence 1 Protein

Limited options are available for treating patients with advanced prostate cancer (PC). Melanoma differentiation associated gene-7/interleukin-24 ( mda -7/IL-24), an IL-10 family cytokine, exhibits pleiotropic anticancer activities without adversely affecting normal cells. We previously demonstrated that suppression of the prosurvival Bcl-2 member, myeloid cell leukemia-1 (Mcl-1), is required -7/IL-24–mediated apoptosis carcinomas. Here we demonstrate pharmacological inhibition Mcl-1 expression unique Apogossypol derivative BI-97C1, also called Sabutoclax, sufficient to sensitize tumors -7/IL-24–induced apoptosis, whereas ABT-737, which lacks efficacy in inhibiting Mcl-1, does not cytotoxicity. A combination regimen tropism-modified adenovirus delivered -7/IL-24 (Ad.5/3- -7) and BI-97C1 enhances cytotoxicity human PC cells, including those resistant or alone. The causes autophagy facilitates NOXA- Bim-induced Bak/Bax-mediated mitochondrial apoptosis. Treatment Ad.5/3- -7 significantly inhibits growth xenografts nude mice spontaneously induced Hi-myc transgenic mice. Tumor correlated increased TUNEL staining decreased Ki-67 both prostates These findings derivative, sensitizes PCs cytotoxicity, thus potentially augmenting therapeutic benefit this combinatorial approach toward PC.